Genetic epidemiology of ventricular tachycardia in patients with cardiomyopathy in Kazakhstan: a targeted sequencing study

Ventricular tachycardia (VT) is a common complication in cardiac disorders of different etiology such as coronary heart disease (CHD) and cardiomyopathies. We hypothesized that the underlying molecular mechanism, independent of disease etiology, might originate from a common overlapping pattern of genetic variants in cardiac disease-related genes. <b>Aim:</b> to investigate genetic basis of VT in patients with cardiomyopathy in Kazakhstan using targeted NGS (design of new HaloPlex gene panel). <b>Material and methods.</b> Using a customized HaloPlex Target Enrichment System? (Agilent Technologies, USA) 96 cardiomyopathy associated candidate-genes were enriched and then sequenced on HiSeq2000 platform using 2x150bp paired-end standard sequencing conditions in DNA of 95 patients diagnosed with sporadic (64/95) or familial (26/95) cardiomyopathies (dilated cardiomyopathy (DCM): 37.3%, idiopathic ventricular tachycardia (iVT): 38.9%, CHD with severe episodes of VT: 24.2%, and others: 3%). <b>Results:</b> The candidate gene library design covers a total target region of 463.767kbp with 406.062 analyzable target bases including all exonic and proximal intronic (+/-10bp) sequence and representing by 2,017 target loci. The mean coverage of all 95 samples at the target loci was 707.62-fold. Targeted sequencing and stepwise filtering of the annotated variants identified a total of 319 unique variants in 74 genes totaling up in 475 variants for the overall study group (HGMD listed). More than 50% of the patients carried at least two mutations, irrespective of the clinical phenotype. Furthermore, 215 private (unique) non-synonymous variants were observed in the patient cohort. Prediction scores of the private variants indicated high probability of disease association. Including the newly identified high-probability variants, each patient carried on average >4.8 genetic variants. Interestingly, statistical evaluation revealed no difference in the frequency of genetic variants (HGMD or rare variants) observed for the CHD and the DCM subgroup. The most abundant mutations of the CHD were observed in <i>MYBPC3, DMD, LAMA2, MYH6</i> and <i>GAA</i>. <i>PRKAG2 </i>mutations were overrepresented in the CHD subgroup. <b>Conclusion:</b> Our study indicates that the majority of the investigated patients with cardiomyopathies and VT, irrespective of disease phenotype or subgroup carry multiple disease-linked mutations and additional potentially functional rare variants in cardiac disease genes. We thus have to consider a molecular disease-overlap with converging phenotypes

Prevalence of high-risk human papillomavirus infection and genotype distribution among Kazakhstani women with abnormal cervical cytology

This study aimed to identify the prevalence and distribution of high-risk human papillomavirus (HR-HPV) types among Kazakhstani women with abnormal cervical cytology. A cross-sectional study was performed from May 2019 to June 2020. Cervical samples were collected from women in the different regions of Kazakhstan. A total of 316 patients’ samples were analysed for HR-HPV using real-time multiplex PCR. Cervical cytology abnormalities were reported according to the Bethesda classification. HPV detection by cytology showed a statistically significant association with HPV status and the number of HPV infection types (p  There is a high prevalence of HR-HPV types among Kazakhstani women with abnormal cervical cytology. The most identified types were HPV16, 18, 31, 33 and 52. There is an emergency need to implement an HPV vaccination program to prevent cervical lesion development.</p

Crude and Adjusted Associations with Smear-positive Among 480 Pulmonary Tuberculosis Cases, Kazakhstan, 2012–2014.

<p>Crude and Adjusted Associations with Smear-positive Among 480 Pulmonary Tuberculosis Cases, Kazakhstan, 2012–2014.</p

Study population characteristics among 562 total and smear-positive participants, Kazakhstan, 2012–2014.

<p>Study population characteristics among 562 total and smear-positive participants, Kazakhstan, 2012–2014.</p

<i>RYR2</i> Sequencing Reveals Novel Missense Mutations in a Kazakh Idiopathic Ventricular Tachycardia Study Cohort

<div><p>Channelopathies, caused by disturbed potassium or calcium ion management in cardiac myocytes are a major cause of heart failure and sudden cardiac death worldwide. The human ryanodine receptor 2 (RYR2) is one of the key players tightly regulating calcium efflux from the sarcoplasmic reticulum to the cytosol and found frequently mutated (<60%) in context of catecholaminergic polymorphic ventricular tachycardia (CPVT1). We tested 35 Kazakhstani patients with episodes of ventricular arrhythmia, two of those with classical CPVT characteristics and 33 patients with monomorphic idiopathic ventricular arrhythmia, for variants in the hot-spot regions of the <i>RYR2</i> gene. This approach revealed two novel variants; one de-novo <i>RYR2</i> mutation (c13892A>T; p.D4631V) in a CPVT patient and a novel rare variant (c5428G>C; p.V1810L) of uncertain significance in a patient with VT of idiopathic origin which we suggest represents a low-penetrance or susceptibility variant. In addition we identified a known variant previously associated with arrhythmogenic right ventricular dysplasia type2 (ARVD2). Combining sets of prediction scores and reference databases appeared fundamental to predict the pathogenic potential of novel and rare missense variants in populations where genotype data are rare.</p></div

Allele frequencies of common RYR2 single nucleotide polymorphisms in various study populations.

<p>Allele frequencies of common RYR2 single nucleotide polymorphisms in various study populations.</p

List of nonsynonymous RYR2 single nucleotide variants^*.

<p>*AA: Amino Acid. D: Damaging. VUS: Variant of Unknown Significance. B: Benign. SCD: Sudden Cardiac Death. CD: Cardiac Death.</p

Electropherograms of RYR2 sequences from patients #271 (a), #239 (b), and #444 (c).

<p>Electropherograms of RYR2 sequences from patients #271 (a), #239 (b), and #444 (c).</p

Frequency of RYR2 single nucleotide variants.

<p>KazVTSG: Kazakh Ventricular Tachycardia Study Group (n = 35). KazBCSC: Kazakh Breast Cancer Study Cohort (n = 96). KazCG: Kazakh control group (n = 192). HGMD: Human Genome Mutation Database. ESP6500, the 1000Genomes and the 192 KazCG are negative for the observed RYR2 variants. Variant p.V1810L was detected in 1/96 unrelated female breast cancer patient from the KazBCSC.</p

Information on whole mitochondrial genome sequences which used for comparison.

Information on whole mitochondrial genome sequences which used for comparison.</p